This invention relates generally to a method for synthesizing Group 8 transition metal carbene complexes useful as olefin metathesis catalysts, and more particularly relates to a novel one-pot synthesis of mixed ligand transition metal carbene catalysts that contain a heteroatom-stabilized carbene ligand, e.g., an imidazolylidene ligand. The invention also pertains to a method for synthesizing a precursor to heteroatom-stabilized carbene ligands, particularly 1,3-disubstituted-2-trichloromethyl-5-dihydroimidazolidene.
To the synthetic organic or polymer chemist, simple methods for forming carbon-carbon bonds are extremely important and valuable tools. One method of Cxe2x80x94C bond formation that has proved particularly useful is transition-metal catalyzed olefin metathesis. xe2x80x9cOlefin metathesis,xe2x80x9d as is understood in the art, refers to the metal-catalyzed redistribution of carbon-carbon bonds. See Trnka and Grubbs (2001) Acc. Chem. Res. 34:18-29. Over two decades of intensive research effort has culminated in the discovery of well-defined ruthenium and osmium carbenes that are highly active olefin metathesis catalysts and stable in the presence of a variety of functional groups.
These ruthenium and osmium carbene complexes have been described in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108, 5,969,170, 6,111,121, and 6,211,391 to Grubbs et al., assigned to the California Institute of Technology. The ruthenium and osmium carbene complexes disclosed in these patents all possess metal centers that are formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated. These catalysts are of the general formula (I): 
where M is a Group 8 transition metal such as ruthenium or osmium, X and Xxe2x80x2 are anionic ligands, L and Lxe2x80x2 are neutral electron donors, and R and Rxe2x80x2 are specific substituents, e.g., one may be H and the other may be a substituted or unsubstituted hydrocarbyl group such as phenyl or Cxe2x95x90C(CH3)2. Such complexes have been disclosed as useful in catalyzing a variety of olefin metathesis reactions, including ring opening metathesis polymerization (xe2x80x9cROMPxe2x80x9d), ring closing metathesis (xe2x80x9cRCMxe2x80x9d), acyclic diene metathesis polymerization (xe2x80x9cADMETxe2x80x9d), ring-opening metathesis (xe2x80x9cROMxe2x80x9d), and cross-metathesis (xe2x80x9cCMxe2x80x9d or xe2x80x9cXMETxe2x80x9d) reactions.
For the most part, such metathesis catalysts have been prepared with phosphine ligands, e.g., triphenylphosphine or dimethylphenylphospine, exemplified by the well-defined, metathesis-active ruthenium alkylidene complexes (II) and (III): 
wherein xe2x80x9cCyxe2x80x9d is a cycloalkyl group such as cyclohexyl or cyclopentyl. See U.S. Pat. No. 5,917,071 to Grubbs et al. and Trnka and Grubbs, cited supra. These compounds are highly reactive catalysts useful for catalyzing a variety of olefin metathesis reactions, and are tolerant of many different functional groups. However, as has been recognized by those in the field, the compounds display low thermal stability, decomposing at relatively low temperatures. Jafarpour and Nolan (2000) Organometallics 19(11):2055-2057.
Recently, however, significant interest has focused on the use of N-heterocyclic carbene ligands as superior alternatives to phosphines. See, e.g., Trnka and Grubbs, supra; Bourissou et al. (2000) Chem. Rev. 100:39-91; Scholl et al. (1999) Tetraheron Lett. 40:2247-2250; Scholl et al. (1999) Organic Lett. 1(6):953-956; and Huang et al. (1999) J. Am. Chem. Soc. 121:2674-2678. N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species. In addition, replacement of one of the phosphine ligands in these complexes significantly improves thermal stability. The vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al. (1999) Acc. Chem. Res. 32:913-921). Representative of these second generation catalysts are the four ruthenium complexes (IVA), (IVB), (VA) and (VB): 
In the above structures, Cy is as defined previously, xe2x80x9cIMesxe2x80x9d represents 1,3-dimesityl-imidazol-2-ylidene 
and xe2x80x9cIMesH2xe2x80x9d represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene 
These transition metal carbene complexes, particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure, such as in IMesH2, have been found to address a number of previously unsolved problems in olefin metathesis reactions, particularly cross-metathesis reactions. These problems span a variety of reactions and starting materials.
Previously, synthetic routes to such complexes have involved multiple steps and have required air- and moisture-sensitive carbene precursors as starting materials. Such methods are described, for example, by Scholl et al. (1999) Tet. Lett. 40:2247-2250, Kingsbury et al. (1999) J. Am. Chem. Soc. 121:791-799, and Huang et al. (1999), cited supra. There is, accordingly, a need in the art for a practical, convenient synthesis of catalysts such as (IVA), (IVB), (V), and (VB), possessing an N-heterocyclic carbene ligand, which provides the desired complexes in high yield using air- and moisture-stable precursors. It would also be desirable if such a synthesis were broadly applicable in the manufacture of other mixed ligand metal alkylidenes as well as related complexes, e.g., mixed ligand metal vinylidenes. The present invention is, in part, directed to such a synthesis.
The invention additionally addresses the problems those working in the field have encountered with synthesis of N-heterocyclic carbene reactants used to prepare catalysts such as (VA) and (VB). Early efforts sought to generate free N-heterocyclic carbenes from electron-rich olefins known as enetetraamines (Scheme 1, reaction (a)). Unfortunately, these olefins are typically only slightly more air- and light-stable than their constituent carbenes; they often undergo rapid oxidation in solution. Even when these olefins are oxidatively stable, their thermal cleavage remains debatable, thereby preventing these olefins from serving as protected carbenes. As an additional drawback, these olefins cleave only at extremely high temperatures that are often incompatible with sensitive metal species. The electron-rich nature of enetetramines also led to the investigation of their cleavage by reaction with electrophiles (Scheme 1(b)). Unfortunately, such reactions are generally unsuitable for use in organometallic synthesis, given the possibility of diverse problems. For example, many nucleophilic metal species will not tolerate strong electrophiles (such as CO2 and SO2) that are required in the cleavage reactions. More importantly, the mechanisms of these electrophilic reactions remain poorly understood; the choice of optimal electrophile remains unclear. With these observations, the xe2x80x9celectrophilicxe2x80x9d route appears ill-suited for a general synthesis of N-heterocyclic carbene-coordinated metal species. 
An improved method involves the formation of carbene xe2x80x9cadductsxe2x80x9d by thermal ejection of a leaving group, as illustrated in Scheme 1, reaction (c). In this scheme, the R groups will typically be aryl substituents (e.g., mesitylene) and an optimal xe2x80x9cAxe2x80x9d group is CCl3. Such a synthesis is described by Wanzlick et al. (1961) Chemiche Berichte 94:2389-2393, and involves direct condensation of N,Nxe2x80x2-diaryl-1,2-diamines with chloral (trichloroacetaldehyde), an impractical route since chloral is subject to distribution regulations, preventing its widespread availability.
An improved method for preparing N-heterocyclic carbene reactants useful, inter alia, in the synthesis of metal carbene complexes, would involve readily available reagents, straightforward reaction conditions (e.g., involving non-dry, non-degassed solvents), with generation of any toxic and/or reactive by-products minimized.
The present invention is addressed to the aforementioned needs in the art, and provides new synthetic routes to metal carbene catalysts, particularly Group 8 transition metal complexes containing a heteroatom-stabilized carbene ligand. Such catalysts, as explained above, are highly active catalysts of olefin metathesis reactions, and are advantageous in many respects. The present synthetic methods, which are xe2x80x9cone-potxe2x80x9d syntheses, provide straightforward and convenient routes to obtaining the aforementioned catalysts in high yield using air- and moisture-stable precursors. The methods are also versatile insofar as they are generally applicable in the preparation of a variety of mixed ligand metal carbene complexes.
In one aspect of the present invention, a one-pot synthesis is provided for preparing Group 8 transition metal alkylidene complexes of the formula (V): 
wherein:
M is a Group 8 transition metal, particularly Ru or Os;
X1 and X2 may be the same or different, and are anionic ligands or polymers;
R, R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z)n-Fn where n is zero or 1, Z is a hydrocarbylene, substituted hydrocarbylene and/or heteroatom-containing hydrocarbylene linkage, and Fn is a functional group;
L is any neutral electron donor ligand; and
L1 is a neutral electron donor ligand having the structure of formula (VI): 
X and Y are heteroatoms selected from N, O, S, and P;
p is zero when X is O or S, and is 1 when X is N or P;
q is zero when Y is O or S, and is 1 when Y is N or P;
Q1, Q2, Q3, and Q4 are linkers, e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or xe2x80x94(CO)xe2x80x94;
w, x, y and z are independently zero or 1; and
R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl,
wherein any two or more of X1, X2, L, R, R1, R2, R3, R3A, R4, and R4A can be taken together to form a chelating multidentate ligand.
The method involves, initially, combining a metal complex ML3(X1)2, where M and X1 are as defined above and L3 is a bidentate organic ligand, with: (a) a salt or adduct of L1, which serves as a precursor to the bound ligand (L1) in the final product; (b) a nucleophilic base; and (c) L or a precursor thereto, in (d) the presence of hydrogen gas, under conditions effective to provide the dihydrogen complex (VII): 
in a reaction mixture. Upon completion of the reaction and subsequent cooling, an alkyne of formula (VIII): 
wherein R, R1, R2 and X2 are as defined previously, is gradually added to the dihydrogen complex. An additional base may be added to neutralize the acid generated during formation of the dihydrogen complex (VII) and/or the nucleophilic base selected is one that is effective in this regard as well.
In another aspect of the invention, a method is provided for synthesizing a ligand precursor L1-CCl3 where L1 is a heteroatom-stabilized carbene ligand as defined above, by contacting an ionized, unsaturated analog of L1 with a non-nucleophilic base in the presence of chloroform. In a preferred embodiment, the ligand precursor has the structure of formula (XI): 
in which R3, R4, R8, R8A, R9, and R9A are substituents independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z)n-Fn where n is zero or 1, Z is hydrocarbylene, substituted hydrocarbylene and/or heteroatom-containing hydrocarbylene, and Fn is a functional group such as phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C1-C20 alkylsulfanyl, C5-C20 arylsulfanyl, C1-C20 alkylsulfonyl, C5-C20 arylsulfonyl, C1-C20 alkylsulfinyl, C5-C20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C1-C20 alkoxy, C5-C20 aryloxy, C2-C20 alkoxycarbonyl, C5-C20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C1-C20 thioester, cyano, cyanato, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl, halogen, stannyl, or germyl, any of which, if the substituent permits, may be further substituted with additional hydrocarbyl and/or -(Z)n-Fn moieties, and further wherein any two or more of R3, R4, R8, R8A, R9, and R9A are optionally linked to form a cyclic group.
In this embodiment, the synthetic method involves contacting a compound having the structure of formula (XII): 
with chloroform and a non-nucleophilic base effective to deprotonate the chloroform, wherein, in formula (XII), Xxe2x88x92 is an anionic counterion such as a halide ion. Examples of non-nucleophilic bases include inorganic hydroxides, metal hydrides, and organolithium reagents.
In other aspects of the invention, the ligand precursor (XI) is directly employed in any of a variety of ligand substitution reactions. For example, precursor (XI) may replace a phosphine ligand in a bisphosphine complex such as (X1)(X2)(PR5R6R7)2Mxe2x95x90CRR14 wherein M, X1, X2, and R are defined previously, R5, R6 and R7 are each independently C5-C20 aryl or C1-C10 alkyl, including cycloalkyl, and R14 is independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z)n-Fn where n, Z and Fn are defined earlier. In such a reaction, the bisphosphine complex is contacted with ligand precursor (XI) under conditions effective to provide the transition metal carbene complex (XIII): 
The invention also pertains to other such reactions wherein the trichloromethyl-substituted ligand precursor (XI) is used in an initial ligand substitution reaction, which is thereafter followed by one or more additional synthetic steps, often without need for isolation and purification of intermediates.
I. Definitions and Nomenclature:
It is to be understood that unless otherwise indicated this invention is not limited to specific reactants, reaction conditions, ligands, metal complexes, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
As used in the specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9ca substituentxe2x80x9d encompasses not only a single substituent but also two or more substituents that may be the same or different.
In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:
As used herein, the phrase xe2x80x9chaving the formulaxe2x80x9d or xe2x80x9chaving the structurexe2x80x9d is not intended to be limiting and is used in the same way that the term xe2x80x9ccomprisingxe2x80x9d is commonly used.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a linear, branched or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The term xe2x80x9clower alkylxe2x80x9d intends an alkyl group of 1 to 6 carbon atoms, and the specific term xe2x80x9ccycloalkylxe2x80x9d intends a cyclic alkyl group, typically having 4 to 8, preferably 5 to 7, carbon atoms. The term xe2x80x9csubstituted alkylxe2x80x9d refers to alkyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a difunctional linear, branched or cyclic alkyl group, where xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to 20 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Preferred alkenyl groups herein contain 2 to 12 carbon atoms. The term xe2x80x9clower alkenylxe2x80x9d intends an alkenyl group of 2 to 6 carbon atoms, and the specific term xe2x80x9ccycloalkenylxe2x80x9d intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms. The term xe2x80x9csubstituted alkenylxe2x80x9d refers to alkenyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkenylxe2x80x9d and xe2x80x9cheteroalkenylxe2x80x9d refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9clower alkenylxe2x80x9d include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
The term xe2x80x9calkenylenexe2x80x9d as used herein refers to a difunctional linear, branched or cyclic alkenyl group, where xe2x80x9calkenylxe2x80x9d is as defined above.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a linear or branched hydrocarbon group of 2 to 20 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Preferred alkynyl groups herein contain 2 to 12 carbon atoms. The term xe2x80x9clower alkynylxe2x80x9d intends an alkynyl group of 2 to 6 carbon atoms. The term xe2x80x9csubstituted alkynylxe2x80x9d refers to alkynyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing alkynylxe2x80x9d and xe2x80x9cheteroalkynylxe2x80x9d refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms xe2x80x9calkynylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
The term xe2x80x9calkoxyxe2x80x9d as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an xe2x80x9calkoxyxe2x80x9d group may be represented as xe2x80x94O-alkyl where alkyl is as defined above. A xe2x80x9clower alkoxyxe2x80x9d group intends an alkoxy group containing 1 to 6 carbon atoms. Analogously, xe2x80x9calkenyloxyxe2x80x9d and xe2x80x9clower alkenyloxyxe2x80x9d respectively refer to an alkenyl and lower alkenyl group bound through a single, terminal ether linkage, and xe2x80x9calkynyloxyxe2x80x9d and xe2x80x9clower alkynyloxyxe2x80x9d respectively refer to an alkynyl and lower alkynyl group bound through a single, terminal ether linkage.
The term xe2x80x9carylxe2x80x9d as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety), generally containing in the range of 5 to 24 carbon atoms. Preferred aryl groups contain one aromatic ring or 2 to 4 fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, and the like. xe2x80x9cSubstituted arylxe2x80x9d refers to an aryl moiety substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing arylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d refer to aryl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the terms xe2x80x9caromatic,xe2x80x9d xe2x80x9caryl,xe2x80x9d and xe2x80x9carylenexe2x80x9d include heteroaromatic, substituted aromatic, and substituted heteroaromatic species.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to an aryl group bound through a single, terminal ether linkage. An xe2x80x9caryloxyxe2x80x9d group may be represented as xe2x80x94O-aryl where aryl is as defined above.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group with an aryl substituent, and the term xe2x80x9caralkylenexe2x80x9d refers to an alkylene group with an aryl substituent; the term xe2x80x9calkarylxe2x80x9d refers to an aryl group that has an alkyl substituent, and the term xe2x80x9calkarylenexe2x80x9d refers to an arylene group with an alkyl substituent.
The term xe2x80x9calicyclicxe2x80x9d refers to an aliphatic cyclic moiety, which may or may not be bicyclic or polycyclic.
The term xe2x80x9caminoxe2x80x9d is used herein to refer to the group xe2x80x94NZ1Z2, where each of Z1 and Z2 is independently selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl and heterocyclic.
The terms xe2x80x9chalo,xe2x80x9d halidexe2x80x9d and halogenxe2x80x9d are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms xe2x80x9chaloalkyl,xe2x80x9d xe2x80x9chaloalkenylxe2x80x9d or xe2x80x9chaloalkynylxe2x80x9d (or xe2x80x9chalogenated alkyl,xe2x80x9d xe2x80x9chalogenated alkenyl,xe2x80x9d or xe2x80x9chalogenated alkynylxe2x80x9d) refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
xe2x80x9cHydrocarbylxe2x80x9d refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 20 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term xe2x80x9clower hydrocarbylxe2x80x9d intends a hydrocarbyl group of 1 to 6 carbon atoms, and the term xe2x80x9chydrocarbylenexe2x80x9d intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 20 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species. The term xe2x80x9clower hydrocarbylenexe2x80x9d intends a hydrocarbylene group of 1 to 6 carbon atoms. xe2x80x9cSubstituted hydrocarbylxe2x80x9d refers to hydrocarbyl substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing hydrocarbylxe2x80x9d and xe2x80x9cheterohydrocarbylxe2x80x9d refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, xe2x80x9csubstituted hydrocarbylenexe2x80x9d refers to hydrocarbylene substituted with one or more substituent groups, and the terms xe2x80x9cheteroatom-containing hydrocarbylenexe2x80x9d and heterohydrocarbylenexe2x80x9d refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term xe2x80x9chydrocarbylxe2x80x9d and xe2x80x9chydrocarbylenexe2x80x9d are to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl and hydrocarbylene moieties, respectively.
The term xe2x80x9cheteroatom-containingxe2x80x9d as in a xe2x80x9cheteroatom-containing hydrocarbyl groupxe2x80x9d refers to a hydrocarbon molecule or a hydrocarbyl molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly, the term xe2x80x9cheteroalkylxe2x80x9d refers to an alkyl substituent that is heteroatom-containing, the term xe2x80x9cheterocyclicxe2x80x9d refers to a cyclic substituent that is heteroatom-containing, the terms xe2x80x9cheteroarylxe2x80x9d and heteroaromaticxe2x80x9d respectively refer to xe2x80x9carylxe2x80x9d and xe2x80x9caromaticxe2x80x9d substituents that are heteroatom-containing, and the like. It should be noted that a xe2x80x9cheterocyclicxe2x80x9d group or compound may or may not be aromatic, and further that xe2x80x9cheterocyclesxe2x80x9d may be monocyclic, bicyclic, or polycyclic as described above with respect to the term xe2x80x9caryl.xe2x80x9d
xe2x80x9csubstitutedxe2x80x9d as in xe2x80x9csubstituted hydrocarbyl,xe2x80x9d xe2x80x9csubstituted alkyl,xe2x80x9d xe2x80x9csubstituted aryl,xe2x80x9d and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. Examples of such substituents include, without limitation: functional groups such as halogen, phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C1-C20 alkylsulfanyl, C5-C20 arylsulfanyl, C1-C20 alkylsulfonyl, C5-C20 arylsulfonyl, C1-C20 alkylsulfinyl, C5-C20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C1-C20 alkoxy, C5-C20 aryloxy, C2-C20 alkoxycarbonyl, C5-C20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C1-C20 thioester, cyano, cyanato, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, or boryl, or a metal-containing or metalloid-containing group (wherein the metal may be, for example, Sn or Ge); and the hydrocarbyl moieties C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C5-C20 aryl, C5-C30 aralkyl, and C5-C30 alkaryl.
In addition, the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above. Analogously, the above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.
When the term xe2x80x9csubstitutedxe2x80x9d appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase xe2x80x9csubstituted alkyl, alkenyl and alkynylxe2x80x9d is to be interpreted as xe2x80x9csubstituted alkyl, substituted alkenyl and substituted alkynyl.xe2x80x9d Similarly, xe2x80x9coptionally substituted alkyl, alkenyl and alkynylxe2x80x9d is to be interpreted as xe2x80x9coptionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.xe2x80x9d
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase xe2x80x9coptionally substitutedxe2x80x9d means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
In the molecular structures herein, the use of bold and dashed lines to denote particular conformation of groups follows the IUPAC convention. A bond indicated by a broken line indicates that the group in question is below the general plane of the molecule as drawn (the xe2x80x9cxcex1xe2x80x9d configuration), and a bond indicated by a bold line indicates that the group at the position in question is above the general plane of the molecule as drawn (the xe2x80x9cxcex2xe2x80x9d configuration).
II. General Description of the Ligands and Catalysts Synthesized:
The methods of the present invention may be used to synthesize Group 8 transition metal carbene complexes that include a metal center in a +2 oxidation state, have an electron count of 16, and are penta-coordinated. More specifically, the methods of the present invention are useful in synthesizing compounds having the structure of formula (V): 
as well as compounds that serve as precursors to L1 in the synthesis of complex (V). The various substituents are as follows:
M, which serves as the transition metal center in the +2 oxidation state, is a Group 8 transition metal, particularly ruthenium or osmium. In a preferred embodiment, M is ruthenium.
X1 and X2 may be the same or different, and are anionic ligands or polymers, and may be linked together to form a cyclic group, typically although not necessarily a five- to eight-membered ring. In preferred embodiments, X1 and X2 are each independently hydrogen, halide, or one of the following groups: C1-C20 alkyl, C5-C20 aryl, C1-C20 alkoxy, C5-C20 aryloxy, C3-C20 alkyldiketonate, C5-C20 aryldiketonate, C2-C20 alkoxycarbonyl, C5-C20 aryloxycarbonyl, C2-C20 acyl, C1-C20 alkylsulfonato, C5-C20 arylsulfonato, C1-C20 alkylsulfanyl, C5-C20 arylsulfanyl, C1-C20 alkylsulfinyl, or C5-C20 arylsulfinyl. Optionally, X1 and X2 may be substituted with one or more moieties selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, aryl, and halide, which may, in turn, with the exception of halide, be further substituted with one or more groups selected from halide, C1-C6 alkyl, C1-C6 alkoxy, and phenyl. In more preferred embodiments, X1 and X2 are halide, benzoate, C2-C6 acyl, C2-C6 alkoxycarbonyl, C1-C6 alkyl, phenoxy, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C5-C20 aryl, or C1-C6 alkylsulfonyl. In even more preferred embodiments, X1 and X2 are each halide, CF3CO2, CH3CO2, CFH2CO2, (CH3)3CO, (CF3)2(CH3)CO, (CF3)(CH3)2CO, PhO, MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate. In the most preferred embodiments, X1 and X2 are each chloride. The complex may also be attached to a solid support, such as to a polymeric substrate, and this attachment may be effected by means of X1 and/or X2, in which case X1 and/or X2 is a polymer.
R, R1 and R2 are selected from the group consisting of hydrogen, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), and -(Z)n-Fn where n, Z and Fn are defined previously. R1 and R2 may also be linked to form a cyclic group, which may be aliphatic or aromatic, and may contain substituents and/or heteroatoms. Generally, such a cyclic group will contain 4 to 12, preferably 5 to 8, ring atoms.
In preferred catalysts, R is hydrogen and R1 and R2 are selected from the group consisting of hydrogen, C1-C20 alkyl, C5-C20 aryl, and -(Z)n-Fn where Z is alkylene or substituted alkylene, and Fn is phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C1-C20 alkylsulfanyl, C5-C20 arylsulfanyl, C1-C20 alkylsulfonyl, C5-C20 arylsulfonyl, C1-C20 alkylsulfinyl, C5-C20 arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso, hydroxyl, C1-C20 alkoxy, C5-C20 aryloxy, C2-C20 alkoxycarbonyl, C5-C20 aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl, C1-C20 thioester, cyano, cyanato, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl, halogen, stannyl, or germyl. More preferably, R1 and R2 are selected from the group consisting of hydrogen, C1-C6 alkyl, and C5-C20 aryl.
L is any neutral electron donor ligand, and may or may not be linked to R2 or other substituents within the complex. Examples of suitable L moieties include, without limitation, phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether (including cyclic ethers), amine, amide, imine, sulfoxide, carboxyl, nitrosyl, pyridine, substituted pyridine (e.g., halogenated pyridine), imidazole, substituted imidazole (e.g., halogenated imidazole), pyrazine (e.g., substituted pyrazine), and thioether. In more preferred embodiments, L is a phosphine of the formula PR5R6R7, where R5, R6, and R7 are each independently C5-C2 aryl or C1C10 alkyl, particularly phenyl, primary alkyl, secondary alkyl or cycloalkyl. In the most preferred embodiments, L is selected from the group consisting of xe2x80x94P(cyclohexyl)3, xe2x80x94P(cyclopentyl)3, xe2x80x94P(isopropyl)3, xe2x80x94P(phenyl)3, xe2x80x94P(phenyl)2(R7) and xe2x80x94P(phenyl)(R7)2, in which R7 is alkyl, typically lower alkyl. Also preferred are weaker ligands such as the nitrogen-containing heterocycles, which enhance catalytic activity presumably because of the requirement that the L ligand dissociate for initiation to occur. Examples of complexes wherein L and R2 are linked include the following: 
L1 is a neutral electron donor ligand having the structure of formula (VI): 
wherein X, Y, p, q, Q1, Q2, Q3, Q4, R3, R3A, R4, R4A, w, x, y and z are as follows:
X and Y are heteroatoms typically selected from N, O, S, and P. Since O and S are divalent, p is necessarily zero when X is O or S, and q is necessarily zero when Y is O or S. However, when X is N or P, then p is 1, and when Y is N or P, then q is 1. In a preferred embodiment, both X and Y are N.
Q1, Q2, Q3, and Q4 are linkers, e.g., hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or xe2x80x94(CO)xe2x80x94, and w, x, y and z are independently zero or 1, meaning that each linker is optional. Preferably, w, x, y and z are all zero.
R3, R3A, R4, and R4A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, wherein R3A and R4A may be linked to form a cyclic group.
It should be emphasized that any two or more (typically two, three or four) of X1, X2, L, R1, R2, R3, R3A, R4, and R4A can be taken together to form a chelating multidentate ligand, as disclosed, for example, in U.S. Pat. No. 5,312,940 to Grubbs et al. Examples of bidentate ligands include, but are not limited to, bisphosphines, dialkoxides, alkyldiketonates, and aryldiketonates. Specific examples include xe2x80x94P(Ph)2CH2CH2P(Ph)2xe2x80x94, xe2x80x94As(Ph)2CH2CH2As(Ph2)xe2x80x94, xe2x80x94P(Ph)2CH2CH2C(CF3)2Oxe2x80x94, binaphtholate dianions, pinacolate dianions, xe2x80x94P(CH3)2(CH2)2P(CH3)2xe2x80x94 and xe2x80x94OC(CH3)2(CH3)2COxe2x80x94. Preferred bidentate ligands are xe2x80x94P(Ph)2 CH2CH2P(Ph)2xe2x80x94 and xe2x80x94P(CH3)2(CH2)2P(CH3)2xe2x80x94. Tridentate ligands include, but are not limited to, (CH3)2NCH2CH2P(Ph)CH2CH2N(CH3)2. Other preferred tridentate ligands are those in which any three of X1, X2, L, R1, R2, R3, R3A, R4, and R4A (e.g., X, L, and any one of R3, R3A, R4, and R4A) are taken together to be cyclopentadienyl, indenyl or fluorenyl, each optionally substituted with C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 alkyl, C5-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyloxy, C2-C20 alkynyloxy, C5-C20 aryloxy, C2-C20 alkoxycarbonyl, C1-C20 alkylthio, C1-C20 alkylsulfonyl, or C1-C20 alkylsulfinyl, each of which may be further substituted with C1-C6 alkyl, halogen, C1-C6 alkoxy or with a phenyl group optionally substituted with halogen, C1-C6 alkyl or C1-C6 alkoxy. More preferably, in compounds of this type, X, L, and any one of R3, R3A, R4, and R4A are taken together to be cyclopentadienyl or indenyl, each optionally substituted with vinyl, C1-C10 alkyl, C5-C20 aryl, C1-C10 carboxylate, C2-C10 alkoxycarbonyl, C1-C10 alkoxy, C5-C20 aryloxy, each optionally substituted with C1-C6 alkyl, halogen, C1-C6 alkoxy or with a phenyl group optionally substituted with halogen, C1-C6 alkyl or C1-C6 alkoxy. Most preferably, X, L, and any one of R3, R3A, R4, and R4A may be taken together to be cyclopentadienyl, optionally substituted with vinyl, hydrogen, Me or Ph. Tetradentate ligands include, but are not limited to O2C(CH2)2P(Ph)(CH2)2P(Ph)(CH2)2CO2, phthalocyanines, and porphyrins.
In a preferred embodiment, w, x, y and z are zero, X and Y are N, and R3A and R4A are linked to form xe2x80x94Qxe2x80x94, such that L1 has the structure of formula (IX): 
wherein Q is a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene linker, and further wherein two or more substituents on adjacent atoms within Q may be linked to form an additional cyclic group, which may be similarly substituted to provide a fused polycyclic structure of two to five cyclic groups. Q is often, although again not necessarily, a two-atom linkage or a three-atom linkage, e.g., xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(Ph)xe2x80x94CH(Ph)xe2x80x94 where Ph is phenyl; xe2x95x90CRxe2x80x94Nxe2x95x90, giving rise to an unsubstituted (when R=H) or substituted (R=other than H) triazolyl group; and xe2x80x94CH2xe2x80x94SiR2xe2x80x94CH2xe2x80x94 (where R is H, alkyl, alkoxy, etc.).
In a more preferred embodiment, Q is a two-atom linkage having the structure xe2x80x94CR8R8Axe2x80x94CR9R9Axe2x80x94 or xe2x80x94CR8xe2x95x90CR9xe2x80x94, more preferably xe2x80x94CR8R8Axe2x80x94CR9R9Axe2x80x94, in which case the complex has the structure of formula (XIV): 
wherein R8, R8A, R9, and R9A are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and may comprise a functional group Fn as defined previously. Preferred R8, R8A, R9, and R9A moieties include, without limitation, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C5-C20 aryl, carboxyl, C1-C20 alkoxy, C2-C20 alkenyloxy, C2-C20 alkynyloxy, C5-C20 aryloxy, C2-C20 alkoxycarbonyl, C2-C20 alkoxycarbonyl, C1-C20 alkylthio, C5-C20 arylthio, C1-C20 alkylsulfonyl, and C1-C20 alkylsulfinyl, optionally substituted with one or more moieties selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C5-C20 aryl, hydroxyl, sulfhydryl, xe2x80x94(CO)xe2x80x94H, and halide.
Additionally, any two of R8, R8A, R9, and R9A may be linked together to form a substituted or unsubstituted, saturated or unsaturated ring structure, e.g., a C4-C12 alicyclic group or a C5 or C6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
Examples of N-heterocyclic carbene ligands incorporated into complex (X) thus include, but are not limited to, the following: 
R3 and R4 are preferably aromatic, substituted aromatic, heteroaromatic, substituted heteroaromatic, alicyclic, or substituted alicyclic, composed of from one to about five cyclic groups. When R3 and R4 are aromatic, they are typically although not necessarily composed of one or two aromatic rings, which may or may not be substituted, e.g., R3 and R4 may be phenyl, substituted phenyl, biphenyl, substituted biphenyl, or the like. In one preferred embodiment, R3 and R4 are the same and have the structure (X): 
in which R10, R11, and R12 are each independently hydrogen, C1-C20 alkyl, substituted C1-C20 alkyl, C1-C20 heteroalkyl, substituted C1-C20 heteroalkyl, C5-C20 aryl, substituted C5-C20 aryl, C5-C20 heteroaryl, C5-C30 aralkyl, C5-C30 alkaryl, or halogen. In especially preferred embodiments, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, halogen, phenyl, and lower alkyl-substituted phenyl. In the most preferred embodiments, R10, R11, and R12 are the same and are each methyl.
Other catalysts may also be synthesized using the present methods, as will be discussed in detail infra. Such catalysts include analogs of alkylidene (V) wherein the Mxe2x95x90CRxe2x80x94CHxe2x95x90CR1R2 moiety is replaced with Mxe2x95x90CRR14 wherein R14 does not necessarily comprise a vinyl group, e.g., it may be alkyl or aryl, and in a preferred embodiment is phenyl. Other complexes that may be synthesized using the methods of the invention are vinylidene analogs of (V) wherein the Mxe2x95x90CRxe2x80x94CHxe2x95x90CR1R2 moiety is replaced with Mxe2x95x90Cxe2x95x90CHR. Both of the latter analogs are readily prepared using a xe2x80x9cchloroform adductxe2x80x9d of a carbene ligand, i.e., a trichloromethyl-substituted precursor to a carbene ligand.
III. One-Pot Synthesis of Transition Metal Alkylidenes:
One embodiment of the invention pertains to a method for synthesizing transition metal alkylidene complexes having the structure of formula (V): 
in which the various substituents are defined earlier herein. The synthesis is a two-step reaction involving formation of a transition metal dihydrogen complex substituted with the desired carbene ligand, followed by reaction with an alkyne to yield the metal alkylidene functionality.
A. Formation of the Dihydrogen Complex Intermediate:
In the initial step of the synthesis, a metal complex ML3(X1)2, where M and X1 are as defined above and L3 is a bidentate organic ligand, is contacted with: (a) a salt or adduct of L1, which serves as a precursor to the bound ligand (L1) in the final product; (b) a nucleophilic base; and (c) L or a precursor thereto, in (d) the presence of hydrogen gas, under conditions effective to provide the dihydrogen complex (VII): 
in a reaction mixture. An additional base may be added to neutralize the acid generated during formation of (VII) and/or the nucleophilic base selected is one that is effective in this regard as well.
The nucleophilic base is generally a nitrogenous base with some steric bulk, as some degree of steric encumbrance typically increases the yield of the dihydrogen complex and minimizes generation of other metal hydride species. Preferred nucleophilic bases contain secondary or tertiary alkyl moieties, cycloalkyl moieties, aryl groups, tri(alkyl)silyl groups, or the like, and particularly preferred nucleophilic bases have the structure M1N(SiR153)2 wherein M1 is an alkali metal, preferably potassium, and R15 is hydrocarbyl, typically lower hydrocarbyl, and thus includes the lower alkyl groups methyl, ethyl, n-propyl, cyclohexyl. Such bases are more effective in the present method when a nonpolar organic solvent such as benzene, toluene, hexane, or the like is employed for the reaction. In addition, with nucleophilic bases of the formula M1N(SiRX3)2, there is generally no need for an additional base to remove the acid generated during formation of the dihydrogen complex, insofar as the HN(SiRx3)2 generated from the deprotonation of the salt or ligand of L1 (e.g., IMesH2Cl), is typically sufficient to remove the acid (e.g., HCl) produced.
In a preferred embodiment, the salt or adduct of L1 is a halide salt, e.g., a chloride salt, or a trichloromethyl-substituted carbene precursor as described in part (IV) of this section, infra. The ligand L3 may be virtually any bidentate ligand that can detach in a ligand substitution reaction with the salt or adduct of L1. Examples of ligands suitable as L3 include C5-C8 cyclic dienes, optionally substituted and/or heteroatom containing. A particularly preferred L3 is 1,5-cyclooctadiene.
Elevated temperatures are generally necessary, on the order of 55xc2x0 C. to 90xc2x0 C., although it will be appreciated that an optimum temperature for any particular reaction will depend on the selected starting materials. Hydrogen pressure in the reaction chamber will generally be maintained at about 20 psi to 30 psi, although the hydrogen pressure is not critical. The progress of the reaction may be monitored via NMR or using any other suitable means.
After cooling, the dihydrogen complex (VII) may be used in the remaining step of the synthesis without isolation and purification, since (VII) is routinely produced in high yield without a significant fraction of other metal hydrides. However, if desired, the dihydrogen complex can be isolated and purified at this point using conventional means, e.g., by column chromatography on silica gel.
B. Formation of the Dihydrogen Complex:
The second step of the reaction involves formation of the alkylidene at the transition metal center. Following preparation of (VII), cooling, and optional isolation and purification of the dihydrogen complex as described in (A), above, an alkyne of formula (VIII) is 
slowly added to the dihydrogen complex (which may be in the reaction mixture following its preparation in (A), or, if the complex has been isolated and purified, may be in solution in a suitable solvent). This reaction is generally, although not necessarily, carried out at a temperature in the range of about 5xc2x0 C. to about 30xc2x0 C. In formula (VIII), R, R1, R2 and X2 are as defined previously.
Suitable alkynes for carrying out this reaction are described in U.S. Patent Publication No. 2002/0022733 A1 to Grubbs et al., and include, by way of example, compounds of formula (VIII) wherein R is hydrogen, C1-C20 alkyl, or C5-C20 aryl, X1 is halide, and R1 and R2 are each C1-C20 alkyl, C5-C20 aryl, C1-C20 alkoxy, C5-C20 aryloxy, C1-C20 alkylsulfanyl, C5-C20 arylsulfanyl, C1-C20 alkylsulfinyl, C5-C20 arylsulfinyl, and may comprise functional groups Fn wherein Fn is defined previously. For any of the R, R1 and R2 moieties that permit further substitution, such moieties may further include substituents and/or heteroatoms that do not adversely affect the desired reaction. Particularly preferred alkynes are the propargylic halides Hxe2x80x94Cxe2x89xa1Cxe2x80x94C(CH3)2X1 wherein X1 is halo, e.g., chloro or bromo.
The reaction between the alkyne and the dihydrogen complex (VII) proceeds quickly, even at a low temperatures. See Example 1, which describes synthesis of the alkylidene complex (PCy3)(IMesH2)Cl2Ruxe2x95x90CHxe2x80x94CHxe2x95x90C(CH3)2 (2) via the dihydrogen complex (PCy3)(IMesH2)Ru(H)(H2)Cl (1). Following formation of (1), addition of propargyl chloride resulted in a nearly instantaneous reaction, yielding the desired alkylidene complex (2) in  greater than 95% yield. Reactions with other alkynes, particularly propargylic halides, also proceed rapidly and afford high yields of the transition metal alkylidene product.
IV. Preparation of xe2x80x9cChloroform Adductsxe2x80x9d As Carbene Ligand Precursors:
In another embodiment, a method is provided for synthesizing a trichloromethyl-substituted ligand precursor having the structure L1-CCl3 wherein L1 is defined in part (I) of this section. In a preferred embodiment, the ligand precursor L1-CCl3 has the structure (XI): 
in which R3, R4, R8, R8A, R9, and R9A are as defined previously. This ligand precursor, or xe2x80x9cchloroform adduct,xe2x80x9d is an optimal precursor to L1 in the synthesis described in part (III), above. That is, compound (XI) serves as the salt or adduct of L1 that is combined with the metal complex, the nucleophilic base, and L.
In this embodiment, an ionized, unsaturated analog of L1 is reacted with chloroform and a base. In a preferred embodiment, compound (XI) is synthesized by contacting a compound having the structure of formula (XII): 
(i.e., the ionized, unsaturated analog of L1) with chloroform and a non-nucleophilic base effective to deprotonate the chloroform. Suitable bases include inorganic hydroxides, metal hydrides, and organolithium reagents such as t-butyllithium. Inorganic hydroxides include, by way of example, alkali metal hydroxides, alkaline earth metal hydroxides, e.g., sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and the like. Preferred inorganic hydroxides are potassium hydroxide and sodium hydroxide, with potassium hydroxide particularly preferred. Metal hydrides include, but are not limited to, sodium hydride, lithium hydride, potassium hydride, rubidium hydride, cesium hydride, magnesium hydride, calcium hydride, strontium hydride, barium hydride, aluminum hydride, and combinations thereof. The metal hydride is preferably sodium hydride. Metal hydrides also include metal borohydrides, for example, lithium borohydride, potassium borohydride and sodium borohydride, although sodium hydride is particularly preferred. Organolithium reagents, as will be appreciated by those of ordinary skill in the art, include alkyllithium reagents such as methyl lithium, isopropyl lithium, n-butyllithium, s-butyllithium, t-butyllithium, and the like, as well as aryllithium lithium reagents, e.g., phenyl lithium and p-tolyl lithium.
The reaction will generally be carried out for a time period of about 0.5 to 4 hours at ambient temperature, although elevated temperatures may be beneficial or required under certain conditions. The chloroform may serve as the solvent, or an additional solvent may be employed. Any organic solvent can be used providing that there is no adverse impact on the desired reaction and that the reactants are sufficiently soluble therein. Suitable solvents include, solely by way of example, benzene, toluene, and tetrahydrofuran.
A series of experiments was carried out to evaluate the effect of various parameters on the aforementioned reaction, as described in Example 6. Chloroform was deprotonated with a variety of non-nucleophilic bases (including alkali metal hydroxides) and the resulting solution was added to the chloride 4,5-dihydroimidazolium salt (IMesH2Cl) under varying temperatures and solvent conditions (Table 1).
After purification by recrystallization or column chromatography, the IMesH2.CHCl3 adduct could be isolated on the gram scale in 83-90% yields as pure crystalline material. This high-yielding adduct synthesis, using the easily handled base potassium hydroxide, represents the simplest procedure developed to date for the production of IMesH2.CHCl3 and analogs thereof. The synthesis can be readily carried out on the benchtop with non-dry, non-degassed solvents, and the use of potassium hydroxide prevents any large-scale flammability or reactivity problems. Exposure to potentially toxic chlorinated solvents (i.e. chloroform) in this procedure is also kept to a minimum.
As noted above, it is also possible to deprotonate chloroform with even stronger non-nucleophilic bases such as organolithium reagents (tert-butyllithium) and florene. These examples are noteworthy for their solubility in other non-polar solvents (such as hexanes or diethyl ether) which may be used. In a variety of cases these nonpolar solvents should be ideal to limit the solubility of the imidazolium salt, thereby minimizing the side reactions from dichlorocarbene formed in the reaction.
The aforementioned adduct synthesis was also found to be tolerant of a variety of substitution patterns on the 4,5-dihydro-imidazolium salt, including R3 and/or R4=substituted aryl and R8 and/or R9=aryl or alkyl (in structural formula (XI)). It is relevant to note that only 4,5-dihydroimidazolium salts form imidazolidenesxe2x80x94the aromatic imidazolium salts (i.e., the unsaturated analogs) never form these adducts under any conditions. Instead, the latter species undergo immediate deprotonation to directly form the free carbene.
An alternate way of obtaining the compound IMesH2.CHCl3 is by the reaction of an equimolar amount of a strong base such as sodium hydride with chloroform in the presence of the salt (II), as described in Example 4, part (a). By this route, higher yield and purity of the obtained product is achievable, eliminating any further purification. This reaction is relatively rapid and takes place at room temperature. The trichloromethyl anion is formed in low concentrations from the reaction of a strong base with chloroform itself. This can be pre-formed, standardized and stored for short a period at low temperature to prevent the formation of dichlorocarbene. Chloroform is also conveniently used as a single component recyclable system because bis-mesityl-imidazolium chloride and like compounds are soluble in it, thus acting as a solvent and reactant the entire reaction. If equimolar amounts of base and imidazolium (or other) salt are dissolved in chloroform, upon dissolution of the base, the trichloromethyl anion is formed and is readily uptaken by the imidazolium salt. In a few minutes, the base is depleted and the resulting product remains in solution while sodium chloride (the only solid byproduct) falls out of solution. This way, the byproducts are minimized, maximizing the yield and avoiding further purification.
Once the adduct (XI) is obtained in large quantity by the described method, it may be directly employed in a variety of ligand substitution reactions. In one embodiment, ligand precursor (XI) may replace a phosphine ligand in a bisphosphine complex such as (X1)(X2)(PR5R6R7)2Mxe2x95x90CRR14, below, 
wherein M is Ru or Os, typically Ru, X1 and X2 are halides or other anionic ligands, R5, R6, and R7 are each independently aryl or C1-C10 alkyl, including cycloalkyl, R is as defined previously, and R14 is independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z)n-Fn where n, Z and Fn are defined earlier. In such a reaction, the bisphosphine complex is contacted with ligand precursor (XI) under conditions effective to provide the transition metal carbene complex (XIII): 
As demonstrated in Table 2, the rate of this substitution reaction is strongly temperature-dependent. In general, the reaction does not proceed at any appreciable rate below 55xc2x0 C. At 80xc2x0 C., the substitution rate remains much slower than the rate of phosphine dissociation, suggesting that the rate-limiting step in these reactions is the decomposition of IMesH2.CHCl3 to the free carbene. Even at these high temperatures the ruthenium species appear to remain intact throughout the reaction, without the formation of hydrides or other byproducts.
Another example of a ligand substitution reaction in which the ligand precursor (XI) has utility is in the synthesis of a transition metal alkylidene complex of formula (XIV): 
wherein M, X1, X2, L, R, R1, R2, R3, R4, R8, R8A, R9, and R9A are as defined previously. The method circumvents the need for an excess of the salt or adduct of L1 (e.g., IMesH2Cl) used as a starting material in the direct substitution reaction described in part (III) of this section (see Example 4). In this embodiment, the route towards the transition metal alkylidene complex (XIV) is carried out as follows.
Initially, the ligand precursor (XI): 
is contacted with a metal complex M(X1)2(L4)2, wherein X1 is as defined previously and L4 is an eta-6 coordinating ligand, e.g., an aromatic or substituted aromatic ligand such as p-cymene, under an inert atmosphere for a time period effective to allow the ligand substitution reaction to go to completion. The intermediate thereby provided, having the structure of formula (XV): 
is then reacted with P(R5R6R7) in the presence of hydrogen and a base, to give the dihydrogen complex (XVI): 
which is then treated with an alkyne of the formula (VIII): 
wherein R, R1, R2 and X2 are as defined previously, as described in part (III) of this section.
The aforementioned method may be modified to provide a transition metal vinylidene product in lieu of the alkylidene (XIV). The vinylidene product will generally have the structure of formula (XVII): 
wherein M, X1, X2, L, R3, R4, R8, R8A, R9, and R9A are as defined previously, and R13 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and -(Z)n-Fn where n is zero or 1, Z is a hydrocarbylene linkage, and Fn is a functional group.
This synthesis is a one-step method wherein intermediate (XV) is prepared as described above, and then directly treated with an alkyne of formula Hxe2x80x94Cxe2x89xa1Cxe2x80x94R13 and a tri-substituted phosphine (or other anionic ligand precursor).
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the invention. It will be appreciated that various modifications may be made to the methodology of the invention, e.g., with respect to reaction conditions, starting materials, substituents, and the like, which will be recognized by those of ordinary skill in the art as within the spirit and scope of the invention.
All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entireties.